Acute Adipose Inflammation as a Contributor to Acute Kidney Injury After Trauma

急性脂肪炎症是创伤后急性肾损伤的一个原因

基本信息

批准号：
8605537
负责人：
Michael G. S. Shashaty
金额：
$ 15.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605537
关键词：
Abdomen Acute Acute Renal Failure with Renal Papillary Necrosis Adipose tissue Admission activity Advisory Committees Affect Animal Model Area Benchmarking Biological Markers Body mass index Caring Chemosensitization Chronic Clinical Clinical Investigator Clinical Research Cohort Studies Complex Coupled Critical Illness Data Databases Densitometry Diabetes Mellitus Distant End stage renal failure Endotoxemia Ensure Environment Epidemiologist Epidemiology Fatty acid glycerol esters Functional disorder Funding Future Gene Expression Profiling Generations Hospitalization Human Hypertension Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Institution Interleukin-6 Intervention Investigation Kidney Knowledge Laboratories Leptin Light Link Measures Mediating Mediator of activation protein Mentors Mentorship Messenger RNA Methodology Modeling Molecular Monocyte Chemoattractant Protein-1 Motion Obesity Organ Pathogenesis Patients Plasma Population Publications Publishing Reporting Research Research Personnel Risk Risk Factors Role Scanning Sepsis Serum Severities Slice Source Stimulus Survivors Techniques Testing Tissue Sample Tissue-Specific Gene Expression Tissues Training Training Programs Trauma Tumor Necrosis Factor-alpha United States Visceral Work X-Ray Computed Tomography adipokines base career development chemokine cohort cytokine high risk human disease injury prevention mortality mouse model new therapeutic target novel patient oriented prevent public health relevance radiologist resistin response response to injury skills stem subcutaneous tissue trauma

项目摘要

DESCRIPTION (provided by applicant): The broad objectives of the proposed project are to: 1) test the hypothesis that a systemic inflammatory response potentiated by adipose tissue underlies the association of obesity with acute kidney injury (AKI) after major trauma, 2) determine if adipose distribution (visceral versus subcutaneous) affects this association, 3) train the applicant in patient-oriented translational AKI research, and 4) provide the applicant with individualized mentoring to ensure his transition to the role of an independent investigator. AKI is common in critical illness. AKI makes ICU care more complex, is associated with a substantial mortality increase, and increases the risk of end stage renal disease in survivors. Over 2 million people are hospitalized for injury each year in the United States, and over one-third of critically ill trauma patients develop AKI. AKI pathophysiology, however, remains incompletely understood. We published a study showing a strong association of body mass index (BMI) with AKI after major trauma. Our additional preliminary studies suggest that excess adipose tissue, not lean mass, explains this association. The evolving understanding of the key role of inflammation in AKI pathogenesis, coupled with recent studies from our institution suggesting adipose tissue is a significant source of inflammatory mediators in response to acute stimuli, point toward adipose potentiation of the systemic inflammatory response to trauma as a potential mechanism underlying the obesity-AKI relationship. This proposal outlines a plan to study this mechanism in an existing cohort of critically ill trauma patients. Leveraging the near-uniform clinical use of computed tomography (CT) unique to this population, the association with AKI of precise CT-based adiposity measures will be determined to confirm the adiposity-AKI association. The association of admission plasma inflammatory mediator levels with both obesity and subsequent AKI will be tested in these subjects. Expression of these mediators will be compared in adipose tissue of trauma patients and healthy controls to test the contribution of adipose to the systemic inflammatory response to trauma and the associated AKI risk. The applicant will engage in a rigorous training program of didactic course work and mentoring by senior epidemiologists, biostatisticians, radiologists, and lab experts. He will gain skills in cohrt study conduct, molecular laboratory techniques, novel obesity measures, advanced statistical methodologies, and renal epidemiology. The applicant's attainment of benchmarks in research, publication, and career development will be regularly reviewed by his mentors and advisory committee. Facilitating the proposed aims is an environment which provides clinical research expertise in a collaborative setting, database and statistical support, and core research labs for plasma and tissue study. Through the conduct of the proposed study and training plan, the applicant will make significant contributions to the understanding of AKI pathophysiology, mature as an investigator, and prepare to compete successfully for R01 funding of future projects aimed at finding novel therapeutic targets tailored to populations at high risk for AKI.

描述（由申请人提供）：拟议项目的广泛目标是：1）检验以下假设：脂肪组织增强的全身性炎症反应是肥胖的关联与急性肾脏损伤（AKI）的关联（AKI），重大创伤后，2）面向患者的转化AKI研究中的申请人，以及4）为申请人提供个性化指导，以确保他向独立研究者的角色过渡。 AKI在危重疾病中很常见。 AKI使ICU护理更加复杂，与大幅度的死亡率增加有关，并增加了幸存者末期肾脏疾病的风险。在美国，每年有超过200万人因受伤而住院，批判性的三分之一以上不良的创伤患者患有AKI。然而，AKI病理生理学仍然尚未完全理解。我们发表了一项研究，显示重大创伤后的体重指数（BMI）与AKI有很强的关联。我们的其他初步研究表明，过量的脂肪组织（而不是瘦质量）解释了这种关联。对炎症在AKI发病机理中的关键作用的不断发展，再加上我们机构的最新研究表明，脂肪组织是响应急性刺激的炎症介质的重要来源，这是对急性刺激的脂肪增强的指向，将创伤的全身性炎症反应作为obesity-obesity-aki-aki关系的潜在机制。该提议概述了在现有的一系列重症创伤患者中研究这种机制的计划。利用该人群独有的计算机断层扫描（CT）的近均匀临床使用，将确定与精确的基于CT的肥胖度量的AKI的关联，以确认肥胖 - AKI关联。入院血浆炎症介质水平与肥胖和随后的AKI的关联将在这些受试者中进行测试。这些介体的表达将在创伤患者的脂肪组织和健康对照组中进行比较，以测试脂肪对全身性炎症反应对创伤和相关AKI风险的贡献。申请人将由高级流行病学家，生物统计学家，放射学家和实验室专家进行严格的教学课程工作和指导。他将获得COHRT研究行为，分子实验室技术，新型肥胖测量，晚期统计方法和肾脏流行病学的技能。申请人在研究，出版和职业发展中获得基准的基准将由他的导师和咨询委员会定期审查。促进该目标的环境是一个在协作环境，数据库和统计支持以及血浆和组织研究的核心研究实验室中提供临床研究专业知识的环境。通过拟议的研究和培训计划的进行，申请人将为了解AKI病理生理学的理解做出重大贡献，该研究人员成熟为研究者，并准备成功争夺R01对未来项目的资金，旨在寻找针对AKI高风险的人群量身定制的新型治疗目标。